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Tip5/Baz2a Regulates Chromatin Architecture and Gene Expression to Maintain Self-renewal and Pluripotency of Embryonic Stem Cells [microarray]

ABSTRACT: It is unclear how gene networks that regulate self-renewal and pluripotency of embryonic stem (ES) cells are established. We searched for factors that contribute to forming functional chromatin architecture in ES cells and identified Tip5 (also called Baz2a) as a genome organizer, folding chromatin and recruiting chromatin remodeling/epigenetic factors to genes. Tip5 binds specialized genomic sequences called base-unpairing regions (BURs) and localizes near heterochromatin. Through chromatin looping Tip5 recruits the polycomb-repressive complex 2 (PRC2) subunits and Jarid2 to target genes far from Tip5-bound BURs and alters their histone profiles. In ES cells Tip5 represses PRC2-bound developmental genes and regulates non-PRC2-bound genes that are enriched for G-protein coupled receptor signaling. Tip5 knockdown caused misexpression of these genes important for ES cell maintenance, leading to rapid ES cell differentiation and impaired pluripotency. These data suggest that Tip5 regulates multiple processes through ES cell-specific genome organization to maintain ES cell stemness.

ORGANISM(S): Mus musculus

PROVIDER: GSE70969 | GEO | 2016/07/14

SECONDARY ACCESSION(S): PRJNA290032

REPOSITORIES: GEO

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Tip5/Baz2a Regulates Chromatin Architecture and Gene Expression to Maintain Self-renewal and Pluripotency of Embryonic Stem Cells [ChIP-seq]

Project description:It is unclear how gene networks that regulate self-renewal and pluripotency of embryonic stem (ES) cells are established. We searched for factors that contribute to forming functional chromatin architecture in ES cells and identified Tip5 (also called Baz2a) as a genome organizer, folding chromatin and recruiting chromatin remodeling/epigenetic factors to genes. Tip5 binds specialized genomic sequences called base-unpairing regions (BURs) and localizes near heterochromatin. Through chromatin looping Tip5 recruits the polycomb-repressive complex 2 (PRC2) subunits and Jarid2 to target genes far from Tip5-bound BURs and alters their histone profiles. In ES cells Tip5 represses PRC2-bound developmental genes and regulates non-PRC2-bound genes that are enriched for G-protein coupled receptor signaling. Tip5 knockdown caused misexpression of these genes important for ES cell maintenance, leading to rapid ES cell differentiation and impaired pluripotency. These data suggest that Tip5 regulates multiple processes through ES cell-specific genome organization to maintain ES cell stemness.

2016-07-14 | GSE70974 | GEO

BAZ2A-mediated repression via H3K14ac-marked enhancers promotes prostate cancer stem cells

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Chromatin immunoprecipitation of mouse polycomb group (PcG) proteins in embryonic stem cells

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Regulation of pluripotency and self-renewal of ES cells through epigenetic-threshold modulation and mRNA pruning

Project description:The core pluripotency factors (Oct4, Sox2, and Nanog), the Myc network, and the chromatin-modifying complexes such as PRC2 ensure the pluripotency and self-renewal of ES cells (ESC). How these factors coordinate with one another remains poorly understood. We report that Utf1, a target of Oct4 and Sox2, is a new bivalent chromatin component that buffers poised states of bivalent genes. By limiting PRC2 loading and Histone 3 lysine-27 trimethylation, Utf1 sets proper activation thresholds for bivalent genes. It also promotes nuclear tagging of mRNAs transcribed from insufficiently silenced bivalent genes for cytoplasmic degradation through mRNA de-capping. Whereas these opposing functions of Utf1 allow proper execution of ESC pluripotency, the mRNA pruning function also ensures rapid cell proliferation by blocking the Myc-Arf feedback regulation. Thus, Utf1 is an important regulator that couples the core pluripotency factors with Myc and PRC2 networks to promote proliferation and pluripotency execution of ESCs. First we mapped Utf1 binding sites in ESCs using the biotin-mediated and cross-linked ChIP-sequencing. To investigate how Utf1 might regulate gene expression, we did RNA-seq on WT and Utf1-KO ES cells. Then we did ChIP-seq of Suz12 and H3K27me3 on WT and Utf1-KO ES cells to study whether Utf1 affects PRC2 loading and H3K27me3 modofication, using H3 as control. Finally, we did RNAseq on WT and Dcp1a-KD ES cells to confirm Utf1 repress gene expression by recruiting Dcp1a complex.

2012-10-26 | E-GEOD-39513 | biostudies-arrayexpress

Regulation of pluripotency and self-renewal of ES cells through epigenetic-threshold modulation and mRNA pruning

2012-10-26 | GSE39513 | GEO

BAZ2A safeguards genome architecture of ground-state pluripotent stem cells

Project description:Chromosomes have an intrinsic tendency to segregate into compartments, forming long-distance contacts between loci of similar chromatin states. How genome compartmentalization is regulated remains elusive. Here, comparison of mouse ground-state embryonic stem cells (ESCs) characterized by open and active chromatin, and advanced serum ESCs with a more closed and repressed genome, reveals distinct regulation of their genome organization due to differential dependency on BAZ2A/TIP5, a component of the chromatin remodeling complex NoRC. On ESC chromatin, BAZ2A interacts with SNF2H, DNA topoisomerase 2A (TOP2A) and cohesin. BAZ2A associates with chromatin subdomains within the active A compartment, which intersect through long-range contacts. We found that ground-state chromatin selectively requires BAZ2A to limit the invasion of active domains into repressive compartments. BAZ2A depletion increases chromatin accessibility at B compartments. Furthermore, BAZ2A regulates H3K27me3 genome occupancy in a TOP2A-dependent manner. Finally, ground-state ESCs require BAZ2A for growth, differentiation, and correct expression of developmental genes. Our results uncover the propensity of open chromatin domains to invade repressive domains, which is counteracted by chromatin remodeling to establish genome partitioning and preserve cell identity.

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Project description:Pluripotent embryonic stem (ES) cells constitute an essential cellular niche in animal development. It is well documented that ES cells are sustained by epigenetic and transcriptional regulation, but the role of post-transcriptional processes remains less explored. Here, we identify a link between nuclear RNA levels, regulated by the ‘polyA RNA exosome targeting’ (PAXT) connection, and transcriptional control, regulated by the Polycomb Repressive Complex 2 (PRC2). Knockout of the PAXT component ZFC3H1 in mouse ES cells impairs their differentiation. In addition to the upregulation of bona fide PAXT substrates, Zfc3h1-/- cells abnormally express developmental genes usually subjected to PRC2-mediated repression. Such de-repression is paralleled by decreased PRC2 binding to chromatin at target genes, and low PRC2-directed H3K27 methylation. PRC2 complex stability is compromised in Zfc3h1-/- cells with elevated levels of unspecific RNA bound to PRC2 components. We propose that excess RNA hampers PRC2 function through its sequestration from DNA and complex destabilisation. Our results highlight the importance of balancing nuclear RNA levels and demonstrate the capacity of bulk RNA to regulate chromatin-associated proteins.

2019-11-12 | GSE137491 | GEO

Chromatin immunoprecipitation of human PolII and SUZ12 proteins in embryonic stem cells

Project description:Polycomb group proteins are essential for early development in metazoans but their contributions to human development are not yet well understood. We have mapped the Polycomb Repressive Complex 2 (PRC2) subunit Suz12 across the entire non-repeat portion of the genome in human embryonic stem (ES) cells. We found that Suz12 is distributed across large portions of over two hundred genes encoding key developmental regulators. These genes are occupied by nucleosomes trimethylated at histone H3K27, are transcriptionally repressed, and contain some of the most highly conserved non-coding elements in the vertebrate genome. We found that preferential activation of PRC2 target genes occurs during differentiation of ES cells into other cell types. The ES cell transcriptional regulators Oct4, Sox2 and Nanog co-occupied a significant subset of these genes, further supporting a link between repression of developmental regulators and stem cell pluripotency. These results indicate that PRC2 occupies a special set of developmental genes in ES cells that must be repressed to maintain pluripotency and that are poised for activation during ES cell differentiation.

2006-06-14 | E-WMIT-7 | biostudies-arrayexpress

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Project description:The ground state of pluripotency is defined as a basal proliferative state free of epigenetic restriction, represented by mouse embryonic stem cells (ESCs) cultured with two kinase inhibitors (so-called “2i”). Through comparison with serum-grown ESCs, we identify epigenetic features characterizing 2i ESCs by proteome profiling of chromatin including post-translational histone modifications. The most prominent difference is H3K27me3 and its enzymatic writer complex PRC2 that are highly abundant on eu- and heterochromatin in 2i ESCs, with H3K27me3 redistributing outside canonical PRC2 targets in a CpG-dependent fashion. Using PRC2-deficient 2i ESCs, we identify epigenetic crosstalk with H3K27me3, including significant increases in H4 acetylation and DNA methylation. This suggests that the unique H3K27me3 configuration protects 2i ESCs from preparation to lineage priming. Interestingly, removal of DNA methylation in PRC2-deficient 2i ESCs lacking H3K27me3 using 5-azacytidine hardly affected ESC viability and transcriptome, showing that ESCs are independent of both major repressive epigenetic marks.

2018-11-21 | PXD007154 | Pride

Transcription profiling of mouse embryonic stem cells FROM Eed knockout vs control

Project description:The Polycomb group (PcG) gene products mediate heritable silencing of developmental regulators in metazoans, participating in one of two distinct multimeric protein complexes, the Polycomb repressive complexes-1 (PRC1) and -2 (PRC2). PRC2 catalyses trimethylation of histone H3 at lysine 27 (H3K27) which in turn is thought to provide a recruitment site for PRC1. Recent studies demonstrate that mono-ubiquitylation of histone H2A at lysine 119 is important in PcG mediated silencing with the core PRC1 component Ring1A/B functioning as the E3 ligase8. PRC2 has been shown to share target genes with the core transcription network to maintain embryonic stem (ES) cells including Oct4 and Nanog. Here we identify an essential role for PRC1 in repressing developmental regulators in ES cells, and thereby in maintaining ES cell pluripotency. A significant proportion of the PRC1 target genes are also repressed by Oct4. We demonstrate that engagement of PRC1 and PRC2 at target genes is Oct4-dependent and moreover that Ring1B interacts with Oct4. Collectively these results show that PcG complexes are instrumental in Oct4-dependent repression required to maintain pluripotency of ES cells. This study provides a first functional link between a core ES cell regulator and global epigenetic regulation of the genome. Experiment Overall Design: Eed is a protein included in PRC2 (Polycomb repressor complex). Experiment Overall Design: We generated constitutive Eed KO mouse ES cells and observed gene expression using Affymetrix MOE430.2 microarray. Experiment Overall Design: These results were compared with other KO cells of PRC1 proteins (Ring1A, Ring1B) and other proteins in our study.

2008-04-07 | E-GEOD-10574 | biostudies-arrayexpress

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